EFFECT OF VALPROATE, SODIUM 2-PROPYL-4-PENTENOATE AND SODIUM 2-PROPYL-2-PENTENOATE ON RENAL SUBSTRATE UPTAKE AND AMMONIAGENESIS IN THE RAT

Experiments were carried out in the intact functioning rat kidney to s tudy the effect of valproate (VPA), a widely used antiepileptic drug a nd an hyperammonemic agent, but usually without clinical relevance, an d of two of its metabolites, sodium 2-propyl-4-pentenoate (4-en-VPA) a nd sodium 2-propyl-2-pentenoate (2-en-VPA), on the renal production of ammonia and on the renal uptake of glutamine, glutamate and of inhibi tors of renal ammoniagenesis; mainly lactate, fatty acids, ketone bodi es and alpha-ketoglutarate. Administration of VPA and 4-en-VPA stimula ted the uptake of glutamine and glutamate and the production of ammoni a by the rat kidney, resulting in an increase in the renal venous rele ase of ammonia and in a hyperammonemia. By contrast, no hyperammonemia was observed after the administration of 2-en-VPA which stimulated re nal ammoniagenesis to a lesser extent than VPA and 4-en-VPA, resulting in no stimulation of the renal venous release of ammonia. The three c ompounds tested caused, in a qualitatively different but, in terms of substrate carbons, in a quantitatively similar manner, a significant d iminution of the renal uptake of fatty acids, ketone bodies and alpha- ketoglutarate. These results suggest that, in the rat kidney, VPA, 4-e n-VPA and 2-en-VPA stimulate the production of ammonia at least in par t by reducing the renal uptake and metabolism of ammoniagenesis inhibi tors; the more potent stimulation of renal ammoniagenesis caused by VP A and 4-en-VPA also suggest that these compounds exert their stimulato ry effect by an additional mechanism.